Outcome benefits of upfront cytoreductive nephrectomy for patients with metastatic renal cell carcinoma: An analysis of the TriNetX database

Background The role of upfront cytoreductive nephrectomy remains debatable in the present era of tyrosine kinase inhibitors and immune checkpoint inhibitors. Here, we aimed to evaluate the outcomes of metastatic renal cell carcinoma patients treated with upfront CN and modern systemic therapies. Methods Using the TriNetX network database, we identified patients, in the period from 2008 to 2022, who were diagnosed with metastatic renal cell carcinoma, receiving first-line systemic therapies with tyrosine kinase inhibitors or immune checkpoint inhibitors. Their overall survivals were evaluated using the Kaplan-Meier method as well as multivariable regressions. Results We identified 11,094 patients with metastatic renal cell carcinoma. Of them, 2,914 (43%) patients in the tyrosine kinase inhibitor cohort (n = 6,779), and 1,884 (43.7%) in the immune checkpoint inhibitors cohort (n = 4315) underwent upfront cytoreductive nephrectomy. Those receiving upfront cytoreductive nephrectomy showed survival advantages with either tyrosine kinase inhibitor (Hazard ratio 0.722, 95% Confidence interval 0.67–0.73, p<0.001) or immune checkpoint inhibitors (Hazard ratio 65.1, 95% Confidence interval 0.59–0.71, p<0.001). In multivariable analysis, upfront cytoreductive nephrectomy was a factor for improved OS in both cohorts: tyrosine kinase inhibitors (Hazard ratio 0.623, 95% Confidence interval 0.56–0.694, p<0.001) and immune checkpoint inhibitors cohort (Hazard ratio 0.688, 95% Confidence interval 0.607–0.779, p<0.001). Conclusions Upfront cytoreductive nephrectomy was associated with an improved overall survival for patients with metastatic renal cell carcinoma receiving either first-line tyrosine kinase inhibitors or immune checkpoint inhibitors. Our results support a clinical role of upfront cytoreductive nephrectomy in the modern era.


Introduction
Over the past two decades, cytoreductive nephrectomy (CN) has been a standard treatment for patients with metastatic renal cell carcinoma (mRCC).The supporting evidence includes results from several randomized trials showing survival benefits from CN plus interferon treatment compared with interferon therapy alone [1][2][3][4].With the introduction of tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (IO), the treatments for mRCC evolved a lot in the past decade [5][6][7][8].Since the role of CN was established before the era of TKI and IO, it is necessary to reassess its influence on oncological outcomes.
In 2018, the randomized phase III trial CARMENA (Cancer du Rein Me ´tastatiqueNe ´phrectomie et Antiangioge ´niques) showed that treatment outcomes in overall survival (OS) with sunitinib alone is not inferior to CN followed by sunitinib for patients with intermediate-or high-risk mRCC [9].However, subgroup analyses revealed that patients with one risk factor from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) have survival benefits with CN.Several studies showed CN plus TKI is associated with improved OS compared with TKI alone for patients with mRCC [10][11][12][13].Recent ASCO guidelines on mRCC also recommended CN as a treatment option for selected patients [14].
Despite the results of the CARMENA trial, CN remains debated in the era of TKI and IO, while it has been used in clinical practice for mRCC patients.Herein, we conducted a retrospective cohort study to assess the role of upfront CN on survival for patients with mRCC receiving either TKI or IO.

Study design, population and outcomes
A retrospective study was performed using TriNetX network, a global database that provides real-world data of �250 million people.In this study, we used the US Collaborative Network including 57 healthcare organizations across the US.
The primary outcome was OS.OS was defined as the duration from the index date to the date of death from any cause, or censored at the end of study, whichever happened first.

Statistical analyses
Patient baseline characteristics, in case of continuous variables, were expressed as mean and standard deviation (SD), and categorical variables, as number and percentage.For evaluating inter-group differences, Student's t test was used for continuous variables, and chi-square test for categorical variables.Survival was evaluated using Kaplan-Meier methodology with a median OS and 95% confidence interval (95% CI), as well as a log-rank test to evaluate intergroup differences in OS.Logistic regression was used to assess various risk factors for death.All analyses were performed on the TriNetX platform.Statistical significance was set at p <0.05.

Ethics in research
Our study was approved by the institutional review board (IRB) of Taichung Veterans General Hospital (number: SE:22220A).Given information for patient identification was not provided on the TriNetX platform, the IRB waived the requirement for informed consent.

Baseline characteristics
Patient characteristics are shown in Table 1.In total, we identified 11,094 patients with mRCC with most of the patients being white.Of them, 6,779 received TKI therapy (the TKI cohort), and 2,914(43%) of them had CN.Also, 4,315 of these patients received IO therapy (the IO cohort), and 1,884 (43.7%) had CN.In the TKI cohort, the majority of patients receive sunitinib (n = 1,984, 29.2%) and pazopanib (n = 1,947, 28.7%).In the IO cohort, the most frequently used treatments were pembrolizumab (n = 1,558, 36.1%) and nivolizumab (n = 1140, 26.4%).Pei chart of races and first-line systemic therapies in the TKI and IO cohorts was illustrated in Fig 1.
In the TKI cohort, patients receiving CN had significantly more distant metastases and comorbidities when compared with those without CN (all with p<0.001).Similarly, in the IO cohort, patients receiving CN had more instances of hypertension (p<0.001),diabetes mellitus (p = 0.0012), ischemic heart disease (p<0.001), and lung metastasis (p<0.001), while bone metastasis occurred more frequently for patients not receiving CN (p<0.001) (Fig 2).The Eastern cooperative oncology group (ECOG) performance status was better for patients receiving CN in both TKI and IO cohorts (TKI cohort: p = 0.016, IO cohort: p = 0.044).

Outcomes
In the TKI cohort, the median follow-up time was 30.1 months, and in the IO cohort, this was 28.8 months.By the end of this study (December, 2022), 3,540 (52.2%) patients in the TKI cohort reached primary end point (deaths), and 2,086 (48.3%) in the IO cohort.
In the TKI cohort, for patients with CN, their survival probability at the 12th month was 73.9% [95% confidence interval (CI) 72.1-75.5]compared with 64.9% (95% CI 63.2-66.5)for those without CN.In the IO cohort, for patients with CN, their survival probability at the 12th month was 71.4% (95% CI 69.1-73.5),compared with 60.3% (95% CI 57.8-62.1)for those without CN.In the TKI cohort, their median OS was 38.3 months for patients with CN, and 23.3 months for those without CN.In the IO cohort, their median OS was 40.5 months for patients with CN, and 19.1 months for those without CN.Patients undergoing CN had survival benefits in OS for both TKI [Hazard ratio (HR) 0.722, 95% CI 0.67-0.73,p<0.001] and IO (HR 65.1, 95% CI 0.59-0.71,p<0.001) cohorts (Fig 3).For patients receiving CN, there was no significant difference in OS between TKI and IO cohorts.

Discussion
In the present study, we conducted a retrospective cohort study on the TriNetX platform to evaluate the benefits of upfront CN for patients with mRCC receiving first-line systemic therapy with either TKI or IO.We found that patients receiving upfront CN, compared with those without CN, were associated with improved OS. CN was historically the standard care option for patients with mRCC.Its evidence is based on several trials reporting survival benefits of surgical intervention in the era of cytokines [1][2][3][4].With the advent of targeted therapies and immune checkpoint inhibitors, several studies reported survival advantages of these new systemic treatments over traditional cytokines [5][6][7][8].Given the rapid evolution of these novel and more efficient agents, the role of CN has become controversial.CARMENA, a phase 3, randomized trial on patients with mRCC, reported that sunitinib alone is not inferior in OS when compared with CN followed by sunitinib [9].SURTIME is a randomized trial, which demonstrated a survival advantage of deferred CN compared with immediate CN, indicating that surgical intervention could be an option for patients with objective response to sunitinib [10].Nevertheless, a subgroup analysis in the CARMENA trial reported that patients with one IMDC risk factor have survival benefit from CN, and multiple studies also supported the role of CN in the modern era [11][12][13][14][15][16][17].In this study, we found that patients undergoing upfront CN were associated with better OS in both TKI and IO cohorts [18,19].One hypothesis of the underlying mechanisms is that primary RCC releases cytokines to stimulate inflammation, and they also reducing immune responses against the tumor [20,21].CN reduces cytokines and prevents metastatic tumors from progression.The potential immune modulation effects of surgery may be further aggravated in patients treated with IO therapies.According to previous studies, patients with fewer sites of metastases and better performance status have survival benefit from surgical intervention [9,13,22,23].In this study, we found that patients receiving CN have better ECOG performance.Interestingly, they had more incidences of distant metastases and co-morbidities.Multiple variables analyses confirmed that fewer metastases and CN were associated with better OS.Results indicated that patients with more distant metastases and co-morbidities may still get survival benefit from surgery.The discrepancy of these findings highlighted the survival advantages of CN in mRCC, suggesting that multiple factors should be considered for clinicians in evaluating these patients.
There are some limitations of our study.First, its retrospective design and non-randomization are subject to selection bias.Second, some patient information and statistics analyses were not available on the platform, such as IMDC risk stratification and Cox regression analysis.Despite these limitations, our study involved a large population in a real-world setting.Our findings provide clinicians some useful information in the management of these patients while awaiting the results from the ongoing trials that assess the role of CN in the era of TKI and IO.

Conclusion
Results of our study supported the OS benefits of upfront CN for mRCC patients in the modern TKI and IO era.Before reports emerge from prospective and randomized trials, our findings are helpful for clinicians in treating these patients.